INCREASED SENSITIVITY OF ADRIAMYCIN-SELECTED TUMOR LINES TO CTL-MEDIATED LYSIS RESULTS IN ENHANCED DRUG-SENSITIVITY

The emergence of drug resistance to chemotherapeutic agents is a major cause of treatment failure in cancer therapy. Therefore, much effort has been aimed at circumventing or reversing this undesired effect. Re cently, we found that tumor cell lines selected for their multidrug-re sistant phenotype can also exhibit increased levels of TAP mRNA and MH C class I proteins. This raised the question of whether drug-resistant tumors are more readily recognized by MHC-restricted CTLs. In this re port, we show that five of five MNC class I+ tumor cell lines grown in medium containing Adriamycin developed into variants that expressed h igher levels of MHC class I than did their corresponding parental cell lines. This was not observed with a MHC class I- cell line. No simila r association was noted for changes in the expression of either HER-2 or intercellular adhesion molecule 1 protein. We also found that MHC c lass I+ drug-selected variants were more readily lysed by MHC-restrict ed, tumor-associated CTLs than were the drug-sensitive parental cell l ines. When the drug-selected variants were cocultured with the same CT Ls to eliminate tumor cells expressing higher levels of MHC-I (MHC-I-h i), the CTL-resistant tumor cells exhibited a drug sensitivity profile similar to that of the parental cell lines that were not exposed to A driamycin. These findings suggest that certain chemotherapeutic drugs may increase the immunogenicity of some tumors, and that CTL immunothe rapy may help reverse drug resistance.